System and method for controlling focused ultrasound treatment

ABSTRACT

A system and method for controlling the delivery of ultrasound energy to a subject is provided. In particular, such a system and method are capable of safely disrupting the blood-brain barrier. Ultrasound energy is delivered to produce cavitation of an ultrasound contrast agent at a selected pressure value. An acoustic signal is acquired following cavitation, from which a signal spectrum is produced. The signal spectrum is analyzed for the presence of harmonics, such as subharmonics or ultraharmonics. When subharmonics or ultraharmonics are present, the pressure value is decreased for subsequent sonications. If a previous sonication resulted in no subharmonics or ultraharmonics being generated, then the pressure value may be increased. In this manner, the blood-brain barrier can be advantageously disrupted while mitigating potentially injurious effects of the sonication.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication Ser. No. 61/502,559 filed on Jun. 29, 2011, and entitled“System and Method For Controlling Focused Ultrasound Treatment.”

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

This invention was made with government support under EB003268 andEB000705 awarded by the National Institutes of Health. The governmenthas certain rights in the invention.

BACKGROUND OF THE INVENTION

The field of the invention is systems and methods for focusedultrasound. More particularly, the invention relates to systems andmethods for controlling the delivery of focused ultrasound.

Focused ultrasound (“FUS”) disruption of the blood-brain barrier (“BBB”)using circulating microbubbles is a field of increasing research withthe potential to revolutionize treatment of brain and central nervoussystem (“CNS”) disorders. The BBB prevents passage of molecules from thevasculature into the brain tissue when the molecules are larger thanaround five hundred Daltons, thereby significantly reducing the efficacyof pharmaceutical and other agents.

FUS disruption of the BBB has been successfully used to deliveramyloid-beta antibodies, as described by J. F. Jordao, et al., in“Antibodies Targeted to the Brain with Image-Guided Focused UltrasoundReduces Amyloid-Beta Plaque Load in the TgCRND8 Mouse Model ofAlzheimer's Disease,” PLoS One 2010; 5:e10549; large moleculechemotherapy agents, as described by M. Kinoshita, et al., in“Noninvasive Localized Delivery of Herceptin to the Mouse Brain byMRI-Guided Focused Ultrasound-Induced Blood-Brain Barrier Disruption,”Proc. Natl. Acad. Sci. USA, 2006; 103:11719-11723; and other largemolecules of clinically relevant size, as described by J. J. Choi, etal., in “Molecules of Various Pharmacologically-Relevant Sizes Can Crossthe Ultrasound-Induced Blood-Brain Barrier Opening In Vivo,” UltrasoundMed. Biol., 2010; 36:58-67.

Currently, the greatest limitation for the clinical translation of FUSBBB disruption (“BBBD”) is the lack of a real-time technique formonitoring the delivery of FUS to the subject. Disruption can beevaluated using contrast-enhanced magnetic resonance imaging (“MRI”),but such methods provide insufficient temporal resolution to providereal-time feedback.

The introduction of ultrasound contrast agents, such as microbubblecontrast agents, to the brain can be seen as a safety concern,especially when using transcranial FUS. Moreover, the use of ultrasoundin the skull cavity has been known to make estimation of in situpressure magnitudes and distributions more difficult, as described by M.A. O'Reilly, et al., in “The Impact of Standing Wave Effects onTranscranial Focused Ultrasound Disruption of the Blood-Brain Barrier ina Rat Model,” Phys. Med. Biol., 2010; 55:5251-5267. This increaseddifficulty in pressure estimation when using transcranial ultrasoundhighlights the need for a real-time technique to monitor the microbubblebehavior during FUS induced BBBD.

Studies have been conducted to examine the effects of various acousticand contrast agent parameters on BBBD in an attempt to identify optimaldisruption parameters. For example, see the studies described by F.-Y.Yang, et al., in Quantitative Evaluation of the Use of Microbubbles withTranscranial Focused Ultrasound on Blood-Brain-Barrier Disruption,”Ultrason. Sonochem., 2008; 15:636-643; by N. McDannold, et al., in“Effects of Acoustic Parameters and Ultrasound Contrast Agent Dose onFocused-Ultrasound Induced Blood-Brain Barrier Disruption,” UltrasoundMed. Biol., 2008; 34:930-937; by R. Chopra, et al., in “Influence ofExposure Time and Pressure Amplitude on Blood-Brain-Barrier Openingusing Transcranial Ultrasound Exposures,” ACS Chem. Neurosci., 2010;1:391-398; and by J. J. Choi, et al., in “Microbubble-Size Dependence ofFocused Ultrasound-Induced Blood-Brain Barrier Opening in Mice In Vivo,”IEEE Trans. Biomed. Eng., 2010; 57:145-154.

Other studies have preferred to examine the microbubble emissions duringBBBD in order to identify an emissions characteristic that couldidentify an appropriate treatment endpoint. For example, a sharpincrease in harmonic emissions during sonications resulting insuccessful BBBD has been observed, as described by N. McDannold, et al.,in “Targeted Disruption of the Blood-Brain Barrier with FocusedUltrasound: Association with Cavitation Activity,” Phys. Med. Biol.,2006; 51:793-807. In another study, the presence of the fourth and fifthharmonics where observed when BBBD occurred, as described by Y.-S. Tung,et al., in “In Vivo Transcranial Cavitation Threshold Detection DuringUltrasound-Induced Blood-Brain Barrier Opening in Mice,” Phys. Med.Biol., 2010; 55:6141-6155. It was observed that these higher harmonicswere absent when BBBD was unsuccessful; however, harmonic signal contentcan arise from the tissue or coupling media, and not just thecirculating microbubbles. As a result, these harmonic signal componentsmay not result in the most robust method of controlling treatments.

It would therefore be desirable to provide a system and method forcontrolling the delivery of ultrasound energy to a subject such thatblood-brain barrier disruption can be achieved without injury to thesubject.

SUMMARY OF THE INVENTION

A system and method for controlling the delivery of ultrasound energy toa subject is provided. In particular, such a system and method arecapable of safely disrupting the blood-brain barrier. Ultrasound energyis delivered to produce cavitation of an ultrasound contrast agent at aselected pressure value. An acoustic signal is acquired followingcavitation, from which a signal spectrum is produced. The signalspectrum is analyzed for the presence of harmonics, such as subharmonicsor ultraharmonics. When subharmonics or ultraharmonics are present, thepressure value is decreased for subsequent sonications. If a previoussonication resulted in no subharmonics or ultraharmonics beinggenerated, then the pressure value may be increased. In this manner, theblood-brain barrier can be advantageously disrupted while mitigatingpotentially injurious effects of the sonication.

The foregoing and other aspects and advantages of the invention willappear from the following description. In the description, reference ismade to the accompanying drawings which form a part hereof, and in whichthere is shown by way of illustration a preferred embodiment of theinvention. Such embodiment does not necessarily represent the full scopeof the invention, however, and reference is made therefore to the claimsand herein for interpreting the scope of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a block diagram of an exemplary focused ultrasound (“FUS”)system that can be employed when practicing some embodiments of thepresent invention;

FIG. 2 is a block diagram of another exemplary FUS system that can beemployed when practicing some embodiments of the present invention;

FIG. 3 is a flowchart setting forth the steps of an exemplary method forcontrolling sonications produced by an FUS system such that blood-brainbarrier disruption can be achieved without injury to a subject; and

FIG. 4 is a block diagram of an exemplary magnetic resonance guidedfocused ultrasound (“MRgFUS”) system that is employed when practicingsome embodiments of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

A system and method for controlling the delivery of ultrasound energy toa subject with a focused ultrasound (“FUS”) system is provided.Particularly, ultrasound energy is delivered to the subject in acontrolled manner such that blood-brain barrier disruption can beachieved without injury to the subject. The presence of subharmonics orultraharmonics in the spectral profile of acoustic signals acquiredfollowing the delivery of ultrasound energy to the subject is utilizedto adjust parameters of subsequent sonications, such as acousticpressure. Preferably, microbubble contrast agents are used and theemissions from these microbubbles during sonication are spectrallyanalyzed in real-time to guide subsequent sonications. The providedsystem and method may also be utilized to perform acousticallycontrolled non-thermal lesioning using circulating microbubbles fortreating tumors in near-skull regions where thermal ablation isunachievable. Since the blood-brain barrier is also disrupted in thefocal region during treatment, a therapy agent can also be deliveredafter initial lesioning in order to improve treatment efficacy.

Referring to FIG. 1, an exemplary focused ultrasound (“FUS”) system 100for delivering focused ultrasound to a subject 102 is illustrated. TheFUS system includes a controller 104, an ultrasound transducer 106, anenclosure 108, and a positioning system 110. The enclosure 108 housesthe ultrasound transducer 106 and provides an interface with the subject102 such that ultrasound energy can be efficiently transferred from theultrasound transducer 106 to the subject 102. By way of example, theenclosure 108 is filled with an acoustic coupling medium 112, whichallows for a more efficient propagation of ultrasound energy thanthrough air. Exemplary acoustic coupling media 112 include water, suchas degassed water. Advantageously, the ultrasound transducer 106includes a signal detector 114, such as a hydrophone. By way of example,the signal detector 114 may include a wideband polyvinylidene fluoride(“PVDF”) hydrophone, such as those described by M. A. O'Reilly and K.Hynynen in “A PVDF Receiver for Ultrasound Monitoring of TranscranialFocused Ultrasound Therapy,” IEEE Transactions on BiomedicalEngineering, 2010; 57(9):2286-2294. The ultrasound transducer 106 iscoupled to the positioning system 110 by way of a support 116. Thepositioning system 110 is advantageously a three-axis positioning systemthat provides precise and accurate positioning of the ultrasoundtransducer 106 in three dimensions.

The controller 104 generally includes a processor 118, a signalgenerator 120, and a radio frequency (“RF”) amplifier 122. The signalgenerator 120 may include, for example, a function generator, and isconfigured to provide a driving signal that directs the ultrasoundtransducer 106 to generate ultrasound energy. The driving signalproduced by the signal generator 120 is amplified by the RF amplifier122 before being received by the ultrasound transducer 106. Theultrasound transducer 106 may also be a phased array transducer. Whenthe FUS system 100 is used during a magnetic resonance guided FUS(“MRgFUS”) application, the controller 104 can be positioned inside oroutside of the magnet room of the magnetic resonance imaging (“MRI”)system.

The processor 118 is in communication with the signal generator 120 anddirects the signal generator 120 to produce the driving signal that isdelivered to the ultrasound transducer 106. As will be described belowin detail, the processor 118 may be configured to adjust properties ofthe driving signal such that the ultrasound energy pressure produced bythe ultrasound transducer 106 is adjusted in accordance with embodimentsof the present invention. For example, the processor 118 may beconfigured to use information related to whether harmonics wereidentified in a signal spectrum, as described below, to adjust at leastone of a frequency, a burst length, a pulse repetition frequency, asonication start time, a sonication end time, sonication duration.

The processor 118 receives acoustic signals from the signal detector114. As will be described below in detail, the feedback informationprovided by the signal detector 114 is utilized by the processor 118 todirect the appropriate adjustments in ultrasound energy. The processor118 is also in communication with the positioning system 110, and isconfigured to direct the positioning system 110 to move the position ofthe ultrasound transducer 106 during a sonication procedure. In the casethat the ultrasound transducer 106 is a phased array transducer, thecontroller 104 may adjust the phase and/or amplitude of the driving RFsignal to each transducer element to control the location of the focalspot. The processor 118 may also be in communication with a power meter150. In this configuration, the processor is configured to receivereflected electrical power data from the power meter and to analyze thereflected electrical power data to determine whether an ultrasoundcontrast agent is circulating through a volume-of-interest in thesubject.

The ultrasound transducer 106 is preferably a spherically-focusedtransducer matched to a desired frequency using an external matchingcircuit. In some configurations, the ultrasound transducer 106 isdesigned so that the signal detector 114 may be mounted in the center ofthe ultrasound transducer 106.

Referring now to FIG. 2, in some instances, an FUS system 200 may beconfigured more particularly for transcranial ultrasound applications inhuman subjects. In such a system, a subject 202 receives ultrasoundenergy from a transducer 206 that is configured to surround an extent ofthe subject's head. For example, the transducer 206 may be ahemispherical array of transducer elements. The FUS system 200 mayinclude a cooling system, such as a sealed water system with an activecooling and degassing capacity, so that an appropriate and comfortabletemperature of the skull and skin of the subject 202 may be maintainedduring treatment.

The FUS system 200 includes a processor 218 that is in communicationwith a multi-channel amplifier 224 and a multi-channel receiver 226. Themulti-channel amplifier 224 received driving signals from the processor218 and, in turn, directs the transducer elements of the transducer 206to generate ultrasound energy. The multi-channel receiver 226 receivesacoustic signals during sonications and relays these signals to theprocessor 218 for processing in accordance with embodiments of thepresent invention. The processor 218 may also be configured to adjustthe driving signals in response to the acoustic signals received by themulti-channel receiver 226. For example, the phase and/or amplitude ofthe driving signals may be adjusted so that ultrasound energy is moreefficiently transmitted through the skull of the subject 202 and intothe target volume-of-interest 230. Furthermore, the acoustic signals mayalso be analyzed to determine whether and how the extent of the focalregion should be adjusted. As will be described below in detail,magnetic resonance imaging (“MRI”) may also be used to guide theapplication of ultrasound energy to the subject 202. Thus, an MRIsystem, generally indicated as dashed box 232, may be used to acquiredMRI images 234 of the subject 202. The MRI images 234 may then beprovided to the processor 218 to adjust the parameters of thesonications. For example, the phase and/or amplitude of the drivingsignals may be adjusted so that ultrasound energy is more efficientlytransmitted through the skull of the subject 202 and into the targetvolume-of-interest 230. It is noted that other imaging modalities, suchas computed tomography (“CT”), positron emission tomography (“PET”),single-photon emission computed tomography (“SPECT”), and ultrasound mayalso be used to guide the treatment.

Referring now to FIG. 3, a flowchart setting forth the steps of anexemplary method for controlling a focused ultrasound (“FUS”) system isillustrated. This method for controlling an FUS system provides for thedelivery of ultrasound energy to a subject so that an advantageousdisruption of the blood-brain barrier is achieved without injury to thesubject. First, a contrast agent is administered to the subject, asillustrated at step 302. Exemplary contrast agents include microbubbleultrasound contrast agents, such as those marketed under the nameDefinity® (Lantheus Medical Imaging; North Billerica, Mass.). As thecontrast agent is circulating through the subject, ultrasound energy isdelivered to a target volume using a focused ultrasound (“FUS”) system,as indicated at step 304. The ultrasound energy is delivered withdelivery parameters, such as acoustic power, that are selected so as toproduce a desired pressure in the target volume. By way of example, thedelivery of ultrasound energy, or “sonication,” may be performed usingcontinuous wave bursts having a fundamental frequency of 551.5 kHz.Acoustic signal data is acquired following the delivery of theultrasound energy, as indicated at step 306. This signal data is thenprocessed to determine whether the ultrasound energy delivered in thenext delivery should be adjusted.

The acquired acoustic signal is first transformed into frequency spaceto produce a signal spectrum, as indicated at step 308. For example, afast Fourier transform is applied to the acoustic signal to produce thesignal spectrum. The produced signal spectrum is then analyzed, asindicated at step 310. By way of example, the signal spectrum isintegrated over to identify the presence of harmonics in the signalspectrum. More particularly, the signal spectrum may be analyzed toidentify the presence of subharmonics or ultraharmonics of thefundamental frequency, f₀, of the ultrasound energy, such as 0.5f₀,1.54, and 2.5f₀. By integrating over the signal spectrum around thefrequency values for these subharmonics or ultraharmonics, and comparingthe results with the respective spectral values for a signal spectrumacquired before the contrast agent was administered to the subject, thepresence of the subharmonics or ultraharmonics can be evaluated.

After analyzing the signal spectrum, a determination is made whether oneor more subharmonics or ultraharmonics are present in the signalspectrum, as indicated at decision block 312. If one or moresubharmonics or ultraharmonics are identified in the signal spectrum,then the pressure of the ultrasound energy is decreased before the nextdelivery, as indicated at step 314. For example, the pressure may bedecreased in accordance with:P _(i+1) =γ·P _(i)  (1);

where P_(i) is the pressure used for the i^(th) sonication, P_(i+1) isthe pressure that will be used for the (i+1)^(th) sonication, and γ is afactor that decreases the pressure to a target level as a normalizedvalue of pressure for subharmonic or ultraharmonic emissions. Anexemplary target level of ultrasound energy pressure includes a userselected percentage of the pressure required to induce detectable levelsof subharmonic or ultraharmonic emissions.

After this adjustment, the next ultrasound delivery is performed, andsteps 304-312 may be repeated if more ultrasound energy is to bedelivered to the subject. If no subharmonics or ultraharmonics arepresent in the signal spectrum then a determination is made at decisionblock 316 whether subharmonics or ultraharmonics were present in signalspectra from previous ultrasound energy deliveries. For example, if thefirst sonication results in a signal spectrum with no ultraharmonics,then this information is stored and, following the second sonication,the determination at decision block 316 would be that no ultraharmonicswere present in the previous signal spectrum. If no ultraharmonics wereidentified in the previous signal spectrum, then it may be appropriateto increase the ultrasound energy pressure for the next sonication.Thus, as indicated at step 318, the pressure can be increased. Forexample, the pressure may be increased in accordance with:P _(i+1) =P _(i) +δP  (2);

where δP is an incremental pressure value. If subharmonics orultraharmonics were identified in the previous signal spectrum, then thepressure is maintained at its current level, or reduced depending on thelevel of tissue damage that is desired. If blood-brain barrierdisruption is desired without other effects on tissue, then the pressurelevel may be reduced for the subsequent sonications. If more sonicationsare desired, then the process loops back to perform steps 304-318, asindicated at decision block 320.

Thus, a system and method for actively controlling blood-brain barrierdisruption using acoustic emissions monitoring has been provided. Usingthe provided system and method, it is contemplated that the blood-brainbarrier can be safely disrupted without knowledge of in situ pressures.

The aforementioned FUS treatment can be further monitored and guidedwith the aid of magnetic resonance imaging (“MRI”). To this end, amagnetic resonance guided focused ultrasound (“MRgFUS”) system may beutilized. Referring particularly now to FIG. 4, an exemplary MRgFUSsystem 400 is illustrated. The MRgFUS system 400 includes a workstation402 having a display 404 and a keyboard 406. The workstation 402includes a processor 408, such as a commercially available programmablemachine running a commercially available operating system. Theworkstation 402 provides the operator interface that enables scanprescriptions to be entered into the MRgFUS system 400. The workstation402 is coupled to four servers: a pulse sequence server 410; a dataacquisition server 412; a data processing server 414, and a data storeserver 416. The workstation 402 and each server 410, 412, 414 and 416are connected to communicate with each other.

The pulse sequence server 410 functions in response to instructionsdownloaded from the workstation 402 to operate a gradient system 418 anda radiofrequency (“RF”) system 420. Gradient waveforms necessary toperform the prescribed scan are produced and applied to the gradientsystem 418, which excites gradient coils in an assembly 422 to producethe magnetic field gradients G_(x), G_(y), and G_(z) used for positionencoding MR signals. The gradient coil assembly 422 forms part of amagnet assembly 424 that includes a polarizing magnet 426 and awhole-body RF coil 428.

RF excitation waveforms are applied to the RF coil 428, or a separatelocal coil (not shown in FIG. 4), by the RF system 420 to perform theprescribed magnetic resonance pulse sequence. Responsive MR signalsdetected by the RF coil 428, or a separate local coil (not shown in FIG.4), are received by the RF system 420, amplified, demodulated, filtered,and digitized under direction of commands produced by the pulse sequenceserver 410. The RF system 420 includes an RF transmitter for producing awide variety of RF pulses used in MR pulse sequences. The RF transmitteris responsive to the scan prescription and direction from the pulsesequence server 410 to produce RF pulses of the desired frequency,phase, and pulse amplitude waveform. The generated RF pulses may beapplied to the whole body RF coil 428 or to one or more local coils orcoil arrays (not shown in FIG. 4).

The RF system 420 also includes one or more RF receiver channels. EachRF receiver channel includes an RF amplifier that amplifies the MRsignal received by the coil 428 to which it is connected, and a detectorthat detects and digitizes the I and Q quadrature components of thereceived MR signal. The magnitude of the received MR signal may thus bedetermined at any sampled point by the square root of the sum of thesquares of the I and Q components:M=√{square root over (I ² +Q ²)}  (3);

and the phase of the received MR signal may also be determined:

$\begin{matrix}{\varphi = {{\tan^{- 1}\left( \frac{Q}{I} \right)}.}} & (4)\end{matrix}$

The pulse sequence server 410 also optionally receives patient data froma physiological acquisition controller 430. The controller 430 receivessignals from a number of different sensors connected to the patient,such as electrocardiograph (“ECG”) signals from electrodes, orrespiratory signals from a bellows or other respiratory monitoringdevice. Such signals are typically used by the pulse sequence server 410to synchronize, or “gate,” the performance of the scan with thesubject's heart beat or respiration.

The pulse sequence server 410 also connects to a scan room interfacecircuit 432 that receives signals from various sensors associated withthe condition of the patient and the magnet system. It is also throughthe scan room interface circuit 432 that a patient positioning system434 receives commands to move the patient to desired positions duringthe scan.

The digitized MR signal samples produced by the RF system 420 arereceived by the data acquisition server 412. The data acquisition server412 operates in response to instructions downloaded from the workstation402 to receive the real-time MR data and provide buffer storage, suchthat no data is lost by data overrun. In some scans, the dataacquisition server 412 does little more than pass the acquired MR datato the data processor server 414. However, in scans that requireinformation derived from acquired MR data to control the furtherperformance of the scan, the data acquisition server 412 is programmedto produce such information and convey it to the pulse sequence server410. For example, the data acquisition server 412 may acquire MR dataand processes it in real-time to produce information that may be used tocontrol the acquisition of MR data, or to control the sonicationsproduced by the FUS system.

The data processing server 414 receives MR data from the dataacquisition server 412 and processes it in accordance with instructionsdownloaded from the workstation 402. Such processing may include, forexample: Fourier transformation of raw k-space MR data to produce two orthree-dimensional images; the application of filters to a reconstructedimage; the performance of a backprojection image reconstruction ofacquired MR data; the generation of functional MR images; and thecalculation of motion or flow images.

Images reconstructed by the data processing server 414 are conveyed backto the workstation 402 where they are stored. Real-time images arestored in a data base memory cache (not shown in FIG. 4), from whichthey may be output to operator display 412 or a display 436 that islocated near the magnet assembly 424 for use by attending physicians.Batch mode images or selected real time images are stored in a hostdatabase on disc storage 438. When such images have been reconstructedand transferred to storage, the data processing server 414 notifies thedata store server 416 on the workstation 402. The workstation 402 may beused by an operator to archive the images, produce films, or send theimages via a network to other facilities.

The MRgFUS system may include a patient table with an integratedultrasound transducer 106. Such an ultrasound transducer 106 is operableto perform the herein described method for providing a non-injuriousdisruption of the blood-brain barrier. Similar to the previouslydescribed FUS system, the ultrasound transducer 106 may be housed in anenclosure 108 that is filled with an acoustically conductive fluid, suchas degassed water or a similar acoustically transmitting fluid. Theultrasound transducer 106 is preferably connected to a positioningsystem 110 that moves the transducer 106 within the enclosure 108, andconsequently mechanically adjusts the focal zone of the transducer 106.For example, the positioning system 110 may be configured to move thetransducer 106 within the enclosure 108 in any one of three orthogonaldirections, and to pivot the transducer 106 about a fixed point withinthe enclosure 108 to change the angle of the transducer 106 with respectto a horizontal plane. When the angle of the transducer 106 is altered,the focal distance of the focal zone may be controlled electronically bychanging the phase and/or amplitude of the drive signals provided to thetransducer 106. These drive signals are provided to the ultrasoundtransducer by an FUS control system 104 that includes drive circuitry incommunication with the ultrasound transducer 106 and a controller thatis in communication with the positioning system 110 and drive circuitry.

The top of the enclosure 108 may include a flexible membrane that issubstantially transparent to ultrasound, such as a Mylar, polyvinylchloride (“PVC”), or other plastic materials. In addition, afluid-filled bag (not shown) that can conform easily to the contours ofa patient placed on the table may also be provided along the top of thepatient table.

The present invention has been described in terms of one or morepreferred embodiments, and it should be appreciated that manyequivalents, alternatives, variations, and modifications, aside fromthose expressly stated, are possible and within the scope of theinvention.

The invention claimed is:
 1. A focused ultrasound system comprising: atransducer for delivering ultrasound energy to a subject; a signaldetector for detecting acoustic signals; a processor in communicationwith the transducer and the signal detector, the processor beingconfigured to: receive an acoustic signal from the signal detector;produce a signal spectrum from the received acoustic signal; analyze theproduced signal spectrum to identify whether at least one ofsubharmonics and ultraharmonics are present therein; select a pressurevalue setting using the analyzed signal spectrum by setting an initialvalue for the pressure value setting and after analyzing the signalspectrum: increasing the pressure value setting until at least one ofsubharmonics and ultraharmonics are first identified in the signalspectrum; and decreasing the pressure value setting according to asetting to a target level as a normalized value of pressure for the atleast one of least one of subharmonics and ultraharmonics when at leastone of subharmonics and ultraharmonics are identified in the signalspectrum; and direct the transducer to generate ultrasound energy so asto produce cavitation of an ultrasound contrast agent at the selectedpressure value setting.
 2. The focused ultrasound system as recited inclaim 1 in which the transducer includes a phased array transducer. 3.The focused ultrasound system as recited in claim 2 in which the phasedarray transducer includes at least one ultrasound receiver.
 4. Thefocused ultrasound system as recited in claim 3 in which the at leastone ultrasound receiver is configured to receive a signal and tocommunicate the received signal to the processor such that a location ofthe at least one of subharmonics and ultraharmonics identified in thesignal spectrum can be determined therefrom.
 5. The focused ultrasoundsystem as recited in claim 2 in which the processor is furtherconfigured to adjust at least one of a phase, an amplitude, and afrequency of drive signals provided to the ultrasound transducer so asto control an extent of the ultrasound energy generated by theultrasound transducer.
 6. The focused ultrasound system as recited inclaim 1 in which the processor is further configured to use informationrelated to whether at least one of sub harmonics and ultraharmonics wereidentified in the signal spectrum to adjust at least one of a frequency,a burst length, a pulse repetition frequency, a sonication start time, asonication end time, and a sonication duration.
 7. The focusedultrasound system as recited in claim 1 in which the transducer isconfigured to surround an extent of a head of the subject.
 8. Thefocused ultrasound system as recited in claim 1 in which the processoris further configured to: use the received acoustic signal to determinewhether an ultrasound contrast agent is circulating through avolume-of-interest in the subject; and adjust the selected pressurevalue setting using information related to whether an ultrasoundcontrast agent is circulating through the volume-of-interest in thesubject.
 9. The focused ultrasound system as recited in claim 1 in whichthe processor is configured to analyze the produced signal spectrum at afundamental frequency of the produced signal spectrum in order todetermine whether an ultrasound contrast agent is circulating through avolume-of-interest in the subject.